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Multiple acyl-CoA dehydrogenase deficiency

Disease definition

Multiple acyl-CoA dehydrogenation deficiency (MADD) is a disorder of fatty acid and amino acid oxidation and is a clinically heterogeneous disorder ranging from a severe neonatal presentation with metabolic acidosis, cardiomyopathy and liver disease, to a mild childhood/adult disease with episodic metabolic decompensation, muscle weakness, and respiratory failure.

Summary

Epidemiology

Birth prevalence is estimated at 1/200,000 but great variation is seen between countries/ethnicities.

Clinical description

Patients with MADD fall into 3 broad clinical phenotypes: 1) neonatal onset with congenital anomalies, 2) neonatal onset without anomalies, (together called MADD-severe (S); see this term) and 3) mild and/or late onset (MADD-mild (M); see this term). The first group of MADD-S patients are often premature presenting with severe non-ketotic hypoglycemia, hypotonia, hepatomegaly and severe metabolic acidosis within the first 24 hours of life. They usually have dysplastic kidneys with multiple cysts and may also have facial dysmorphism (low-set ears, high forehead, hypertelorism and hypoplastic midface), rocker-bottom feet and anomalies of external genitalia. Death usually occurs within the first week of life. The second group of patients usually present within the first 24-48 hours of life with hypotonia, tachypnea, hepatomegaly, metabolic acidosis and hypoketotic hypoglycemia. Most die during the first week(s) of life but some have survived for several months, usually dying with severe cardiomyopathy. MADD-M patients show a broad clinical spectrum of disease ranging from onset of intermittent episodes of vomiting, metabolic acidosis and hypoketotic hypoglycaemia (+/- cardiac involvement) during the first few months of life to adolescent/adult presentation with acute Reye-like illness with ketoacidosis and lipid storage myopathy. The latter subgroup often responds to pharmacological doses of riboflavin (rr-MADD).

Etiology

MADD is caused by mutations in the ETFA (15q23-q25), ETFB (19q13.3-q13.4) and ETFDH (4q32-q35) genes which encode the alpha and beta subunits of electron transfer flavoprotein (ETF) and ETF-coenzyme Q oxidoreductase. Dysfunction of either of these two flavoproteins leads to compromised fatty acid oxidation..

Diagnostic methods

Urinary organic acid analysis usually displays various combinations of increased dicarboxylic acids, glutaric acid, ethylmalonic acid, 2-hydroxyglutarate, and glycine conjugates. Blood acylcarnitines show increased C4-C18 species although patients may be severely carnitine depleted, which may limit the degree of these abnormalities. Fibroblast fatty acid oxidation flux and fibroblast acylcarnitine analysis following incubation with palmitic acid is usually abnormal. Final confirmation is by mutation analysis. Newborn screening programs are available in Austria, Belgium, Hungary, Iceland, Portugal and Spain.

Antenatal diagnosis

Prenatal diagnosis is possible when 2 pathogenic mutations have been identified in the family.

Genetic counseling

MADD is an autosomal recessive disorder and genetic counseling is available.

Management and treatment

Treatment for the more severe phenotypes involves restriction of both fat and protein and reliance on a high carbohydrate diet. Strict avoidance of fasting and of other precipitating stresses is essential. Emergency regimens should be available for any metabolic decompensation. Riboflavin supplementation of 100-400 mg/day is a very effective treatment for patients with rr-MADD as is CoQ10 supplementation in some. For moderately severe cases, 3-hydroxybutyrate has been used successfully, but further studies are still needed.

Prognosis

MADD-S is invariably fatal. Milder phenotypes have a more favorable prognosis.

Research activities on this disease

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